| Troponin I protein kinase C phosphorylation sites and ventricular function. | |
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MedLine Citation:
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PMID: 15249182 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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OBJECTIVE: Cardiac Troponin I (cTnI) phosphorylation by protein kinase C (PKC) results in a reduction of maximal actomyosin ATPase activity, an effect that is more marked at higher levels of calcium (Ca2+) and is likely to reduce active force development. We postulated that there would be greater Ca2+-dependent changes in ventricular function in hearts of cTnI transgenic (TG) mice expressing mutant troponin I lacking PKC sites compared to wild-type (WT). METHODS: We studied left ventricular function in isolated perfused hearts over a wide range of left ventricular volumes (Frank-Starling relationships) and mechanical restitution at three levels of perfusate Ca2+ (1.5, 2.5, and 3.5 mM). Manganese-enhanced magnetic resonance imaging (MRI) was used to study in-vivo sarcolemmal Ca2+ influx. The phosphorylation status of cTnI was examined by western blot analysis. RESULTS: Systolic contractile function in TG mice was altered in a calcium-dependent manner such that ventricular contractility was significantly greater in TG mice only at 3.5 mM perfusate Ca2+. The relaxation process and passive mechanical properties were unaltered in TG mice. Mechanical restitution parameters were abnormal in TG mice only at 1.5 mM perfusate Ca2+. In-vivo MRI data demonstrated up to 48% reduction in Mn2+-induced contrast enhancement, indicating reduced sarcolemmal Ca2+ influx. Western blot analysis indicated increased cTnI phosphorylation in TG mice. CONCLUSIONS: (1) TG mice exhibit calcium-dependent positive inotropy without slowed relaxation and this phenotype is mitigated by concomitant (compensatory) changes of reduced intracellular Ca2+ and increased phosphorylation of remaining cTnI sites. (2) The contractile phenotype in TG mice can be interpreted as an amplification of the normal response to changes in cellular Ca2+ observed in WT mice. Thus, PKC phosphorylation sites on cTnI play a role in attenuating contractile responses to changes in intracellular Ca2+. |
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Authors:
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Guy A MacGowan; Caroline Evans; Tom C-C Hu; Dan Debrah; Steven Mullet; Hsiao-Huei Chen; Charles F McTiernan; Alexandre F R Stewart; Alan P Koretsky; Sanjeev G Shroff |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Cardiovascular research Volume: 63 ISSN: 0008-6363 ISO Abbreviation: Cardiovasc. Res. Publication Date: 2004 Aug |
Date Detail:
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Created Date: 2004-07-13 Completed Date: 2004-10-13 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 0077427 Medline TA: Cardiovasc Res Country: Netherlands |
Other Details:
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Languages: eng Pagination: 245-55 Citation Subset: IM |
Copyright Information:
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Copyright 2004 European Society of Cardiology |
Affiliation:
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Cardiovascular Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Blotting, Western / methods Calcium / pharmacology* Cardiac Volume Feedback, Physiological Magnetic Resonance Imaging Mice Mice, Transgenic Myocardial Contraction / drug effects Myocardium / metabolism* Perfusion Phosphorylation Protein Kinase C / metabolism* Sarcolemma / metabolism Systole Troponin I / genetics, metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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HL-03826/HL/NHLBI NIH HHS; HL-68083/HL/NHLBI NIH HHS; Z01 NS002989-08/NS/NINDS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Troponin I; 7440-70-2/Calcium; EC 2.7.11.13/Protein Kinase C |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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